Etsuo Naito

Mutations in the X-linked pyruvate dehydrogenase (E1) α subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency

Defects in the pyruvate dehydrogenase (PDH) complex are an important cause of primary lactic acidosis, a frequent manifestation of metabolic disease in children. Clinical symptoms can vary considerably in patients with PDH complex deficiencies, and almost equal numbers of affected males and females have been identified, suggesting an autosomal recessive mode of inheritance of the disease. However, the great majority of PDH complex deficiencies result from mutations in the X‐linked pyruvate dehydrogenase (E1) α subunit gene (PDHA1). The major factors that contribute to the clinical variation in E1α deficiency and its resemblance to a recessive disease are developmental lethality in some males with severe mutations and the pattern of X‐inactivation in females.

PLASMA ADIPONECTIN LEVELS IN NEWBORNS ARE HIGHER THAN THOSE IN ADULTS AND POSITIVELY CORRELATED WITH BIRTH WEIGHT

objective  The aim of this study was to examine plasma adiponectin concentrations during perinatal the period and their correlations with fetal anthropometric parameters and other hormones.

Dynamic Changes in Serum Leptin Concentrations during the Fetal and Neonatal Periods

We investigated the dynamics of the leptin concentration throughout the perinatal period. Serum leptin concentrations in venous cord blood at different gestational ages were measured in 20 preterm and 139 term newborns, as well as in 143 pregnant women and 24 term newborns at approximately 6 d of life. Leptin concentrations in preterm newborns (mean 4.6 ± 6.9 ng/mL) were lower than those in term newborns (mean 19.6 ± 14.3 ng/mL) and tended to increase according to gestational age and birth weight, especially from the late stage of gestation. Leptin concentrations in pregnant women increased from the first trimester and then remained higher than those in non-pregnant women throughout the remainder of pregnancy even after controlling for body mass index. The leptin concentrations of newborns declined rapidly and were extremely low by approximately 6 d of life (mean 1.9 ± 1.1 ng/mL). These results suggest that fetuses might produce a part of circulating leptin in their own adipocytes and that the relatively high leptin concentrations at birth and their rapid decline in the early neonatal period might reflect the dramatic changes of the hormonal and nutritional state during the perinatal period.

Molecular Analysis of Abnormal Pyruvate Dehydrogenase in a Patient with Thiamine-Responsive Congenital Lactic Acidemia

ABSTRACT: A patient who responded to thiamine therapy with reduction of lactate in the blood and cerebrospinal fluid and clinical improvement was studied. Cultured lymphoblastoid cells of this patient were found to show reduced activities of pyruvate dehydrogenase complex (PDHC) and pyruvate dehydrogenase, decreased affinity of PDHC for thiamine pyrophosphate, and defective activation of PDHC by pyruvate dehydrogenase phosphatase. PDHC deficiency in fibroblasts and biopsied muscle of this patient was also due to the decreased affinity of PDHC for thiamine pyrophosphate. A mutation in the E1α subunit containing the thiamine binding site and serine phosphorylation site regulating the activation/inactivation of PDHC was characterized by the polymerase chain reaction and DNA sequencing. A single A→G transition was identified at position 131, resulting in the substitution of Arg-44 for His-44. This mutation must be a de novo mutation because it was not found in either parents genomic DNA. In this study, we have obtained the first evidence at the molecular level for a mutation of thiamine-responsive PDHC deficiency.

Serial brain imaging analysis of stroke-like episodes in MELAS

We report 2 patients of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and consider the pathophysiology of stroke-like lesions, using magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) on MRI, perfusion imaging on MRI, and 1H magnetic resonance spectroscopy (1H-MRS). In Patient 1, T2-weighted imaging (T2-WI) on MRI at onset and even at 44 days after onset of the stroke-like episode showed high intensity in left parietal, temporal, and occipital lobe lesions. In the temporal lobe lesion, the apparent diffusion coefficient (ADC) at 44 days after onset was higher (average: 1.219x10(-3)mm2/s) than that in a normal region (average: 0.796x10(-3)mm2/s). (1)H-MRS of the left parietal lobe lesion at the same day showed a decrease in N-acetylaspartate/(creatine+phosphocreatine) (NAA/Cr) (0.43) and a peak in lactate. 1H-MRS of the contralateral side at the same day showed NAA/Cr (1.57) and no peak in lactate. Thereafter, ADC gradually decreased and NAA/Cr gradually increased, and the peak in lactate disappeared in the lesion. In Patient 2, T2-WI at onset showed high intensity in bilateral occipital lobe lesions. In the left occipital lobe lesion, ADC at the same day was higher (1.082x10(-3)mm2/s) than that in a normal region (average: 0.841x10(-3)mm2/s). (1)H-MRS of the left occipital lobe lesion at the same day showed a decrease of NAA (3.0mM) and a peak in lactate (13.1mM) (measured by LCModel). In 1H-MRS of the normal left parietooccipital lobe at 4 months before onset, NAA was 7.6mM and there was no peak in lactate (0mM). Perfusion imaging at onset showed high intensity in bilateral occipital lobes, which indicated hyperperfusion in stroke-like lesions. Thereafter, ADC gradually decreased and the peak in lactate partially decreased, and the low concentration of NAA persisted (regardless of the partial recovery) in the lesion. These results suggest that the stroke-like episodes is related to vasogenic edema, hyperperfusion, and neuronal damage. Acute oxidative phosphorylation defect may have a crucial role in the pathophysiology of stroke-like episodes.

Comparison of GAD and ICA512/IA-2 Antibodies at and After the Onset of IDDM

OBJECTIVE Longitudinal changes in GAD antibody (Ab) and ICA512/IA-2 (ICA512) Ab were examined in relation to age at the onset of diabetes and autoimmunity against the thyroid gland. RESEARCH DESIGN AND METHODS GADAb, ICA512Ab, and antithyroid autoantibody were examined at onset in 40 juvenile-onset IDDM patients (17 males, 23 females, age at onset 9.4 ± 4.1 years, range 1.7−20). To assess the changes in antibody levels, 29 patients were followed up with sequential serum samples for up to 5 years. RESULTS At onset, GADAb, ICA512Ab, and antithyroid autoantibody (thyroglobulinAb or thyroid peroxidaseAb) were found in 70, 58, and 25% of the 40 patients, respectively. Prepubertal patients (n = 21) had a significantly higher prevalence and index of ICA512Ab compared with pubertal patients (n = 19) (76 vs. 37%, P = 0.012, and 2.43 ± 2.36 vs. 0.66 ± 1.23, P = 0.011), while GADAb was more prevalent in pubertal patients (57 vs. 84%, P = 0.09). A longitudinal analysis of GADAb and ICA512Ab showed that GADAb levels declined more slowly than those of ICA512Ab (P = 0.008). Patients with continuous extremely high levels of GADAb also had high levels of antithyroid autoantibody. CONCLUSIONS The measurement of ICA512Ab is useful in prepubertal patients, who often show rapid progression of the disease. The presence of autoimmunity against thyroid gland seems to influence the GADAb level but not the ICA512Ab level.

Treatment of chronic congenital lactic acidosis by oral administration of dichloroacetate

Sodium dichloroacetate (DCA) was administered orally at a dose of 50 mg per kg body weight twice or three times per day to a newborn infant with lactic acidosis of unknown cause (patient 1) and to a 15-year-old boy with mitochondrial encephalomyopathy associated with lactic acidosis (patient 2). In patient 1, during treatment with DCA, DCA accumulated in the blood judging from the findings that the urinary excretion of DCA increased cumulatively and the blood lactate level rapidly decreased to the normal range. In patient 2, the blood DCA level gradually increased during treatment to a concentration of 250 µgml−1 and the blood lactate level decreased and was maintained within the normal range. DCA was detected in the brain (25 µg g tissue−1) and the liver, kidney and muscle (33.8, 33.8 and 26.3 µg g tissue−1, respectively) obtained at autopsy of patient 1, and in the cerebrospinal fluid of patient 2 at a concentration of 125 µg ml−1 when the blood concentration was 250 µg ml−1. The lactate levels in the cerebrospinal fluid decreased from 7 and 4mmoll−1 to 2.4 and 2.6 mmoll−1 in patients 1 and 2, respectively. Thus DCA may be useful in clinical treatment of chronic congenital lactic acidosis because it seems to cross the blood-brain barrier. However, it must be given at non-toxic doses, determined by monitoring the concentrations of lactate and DCA in the blood, because orally administered DCA tends to accumulate in tissues.

Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene

Leigh syndrome (LS) is a progressive untreatable degenerating mitochondrial disorder caused by either mitochondrial or nuclear DNA mutations. A patient was a second child of unconsanguineous parents. On the third day of birth, he was transferred to neonatal intensive care units because of severe lactic acidosis. Since he was showing continuous lactic acidosis, the oral supplementation of dichloroacetate (DCA) was introduced on 31st day of birth at initial dose of 50 mg/kg, followed by maintenance dose of 25 mg/kg/every 12 h. The patient was diagnosed with LS due to a point mutation of an A-C at nucleotide 599 in exon 6 in the pyruvate dehydrogenase E1α gene, resulting in the substitution of aspartate for threonine at position 200 (N200T). Although the concentrations of lactate and pyruvate in blood were slightly decreased, his clinical conditions were deteriorating progressively. In order to overcome the mitochondrial or cytosolic energy crisis indicated by lactic acidosis as well as clinical symptoms, we terminated the DCA and administered 0.5 g/kg/day TID of sodium pyruvate orally. We analyzed the therapeutic effects of DCA or sodium pyruvate in the patient, and found that pyruvate therapy significantly decreased lactate, pyruvate and alanine levels, showed no adverse effects such as severe neuropathy seen in DCA, and had better clinical response on development and epilepsy. Though the efficacy of pyruvate on LS will be evaluated by randomized double-blind placebo-controlled study design in future, pyruvate therapy is a possible candidate for therapeutic choice for currently incurable mitochondrial disorders such as LS.

Pyruvate dehydrogenase E1α subunit deficiency in a female patient: evidence of antenatal origin of brain damage and possible etiology of infantile spasms

Enlargement of the lateral ventricles and atrophy of the brain were documented ultrasonographically in utero at as early as 28th week of gestation in a female patient with lactic acidosis due to deficiency of the pyruvate dehydrogenase E1alpha subunit, demonstrating that the changes characteristic of this disease can occur antenatally. The mechanism of infantile spasms in this disease may be linked to mosaicism of the brain cells involving the normal enzyme and the mutant enzyme.

Thiamine-responsive lactic acidaemia: role of pyruvate dehydrogenase complex

Abstract Lactic acidaemia is sometimes associated with a defect of the pyruvate dehydrogenase complex (PDHC), catalysing the thiamine-dependent decarboxylation of pyruvate. The activity of PDHC for different thiamine pyrophosphate (TPP) concentrations was determined in 13 patients with lactic acidaemia, clinically responsive to thiamine treatment in order to assess the role of PDHC in the aetiology of thiamine-responsive lactic acidaemia. Culture of lymphoblastoid cells and skin fibroblasts and muscle biopsies were performed in these 13 patients. The activity of PDHC to sodium dichloroacetate (DCA), known as the activator of PDHC, was also examined. Three groups were identified according to PDHC activity. Group 1 (two patients) displayed very low PDHC activity, which was not increased by DCA. This PDHC activity increased at high TPP concentrations. Group 2 (five patients) displayed below normal PDHC activity at low TPP concentrations, increased by DCA. This PDHC activity became normal at high TPP concentrations. PDHC deficiency in these patients of groups 1 and 2 was due to a decreased affinity of PDHC for TPP. Group 3 included six patients with normal PDHC activity at low as well as high TPP concentrations. This PDHC activity was increased by DCA. Conclusion High concentrations of TPP may be required for maximal activity of PDHC in some patients with lactic acidaemia. The assay of PDHC activity, performed at a low concentration of TPP (1 × 10−4 mM) allows selection of patients with thiamine-responsive lactic acidaemia.